Streptococcus pneumoniae is a Gram positive pathogen which is a major cause of lobar pneumonia, sepsis and meningitis (Burman et at., 1985, Rev. Infect. Dis. 7: 133). This pathogenic bacterium is the most frequent cause of bacterial pneumonia in children of developing countries and accounts for up to 76% of cases in adults (Pennington, 1986, Am. Faro. Physician 33: 153; Johnston, 1991, Revs. Infect. Dis. 13 (Suppl. 6):S509; Musher, 1992, Clin. Infect. Dis. 14: 801). Pneumococci generally enter the host via the nasopharynx where they attach to epithelial cells and in some instances persist for several months (Anderson et al., 1981, Infect. Immun. 32: 311). In experimental models, progression to pneumonia results from spread of the pneumococci by aerosolization and conveyance from the nasopharynx down into the lower respiratory tract.
The early pneumonic lesion is characterized by fluid filled alveoli containing pneumococci, which are frequently seen to line the alveolar walls, a distribution suggestive of a specific interaction promoting retention in the alveolar space (Wood, 1941, J. Exp. Med. 73: 222). Pneumococci readily gain access to the blood circulation from the alveolar space, suggesting an aggressive capability to cross the vascular endothelial cells of the alveolar capillaries (Rake, 1936, J. Exp. Med. 63: 191).
Bacterial adherence to eukaryotic cells commonly involves specific bacterial proteins (adhesins) which recognize host cell glycoconjugates. Adherence of pneumococci to human oral epithelium is inhibited in the presence of the disaccharide N-acetyl-glucosamine-.beta.1-3-galactose (GlcNAc.beta.1-3Gal) suggesting that this carbohydrate can serve as a receptor, perhaps relevant to nasopharyngeal carriage (Anderson et al., 1983, J. Exp. Med. 158: 559). It remains unknown precisely which cell type supports pneumococcal adherence in the alveolar space. Pneumococci have been reported to bind to purified glycoconjugates containing terminal or internal GalNAc.beta.1-4Gal, a structure prevalent in pulmonary secretions and lung tissue (Krivan et al., 1988, Proc. Natl. Acad. Sci. USA 85: 6157). This structure differs significantly in stereochemistry from that proposed for the nasopharyngeal receptor.
The identity of pneumococcal adhesions capable of mediating attachment to the nasopharynx, lung, and vascular endothelium is unknown. Consistent with the ability to readily cause experimental bacteremia, pneumococcal adherence to vascular endothelial cells has been shown to be dose-dependent, rapid and independent of capsular type (Geelen et at., 1993, Infec. Immunol. 61: 1538). Both cell-wall components and protein components contribute roughly equally to this association, but specific pneumococcal ligands remain to be identified (Tuomanen et at., 1985, J. Infect. Dis. 151: 859).
Invasive pneumococcal infection is characterized by particularly intense inflammation induced primarily by components of the pneumococcal cell wall (Tuomanen et al., 1985, J. Infect. Dis. 151: 535; Tuomanen et al., 1985, supra; Tuomanen et al., 1987, Am. Rev. Respir. Dis. 135: 869). Pneumococcal teichoic acid and lipoteichoic acid have the highest inflammatory capacity of all the cell wall components (Cabellos et al., 1992, J. Clin. Invest. 90: 612) and their bioactivity has been shown to be critically dependent on the presence of an unusual component: phosphorylcholine (Tomasz and Saukkonen, 1989, Paediatr. Infect. Dis. J. 8: 902). Phosphorylcholine is also the critical determinant of the biological activity of the inflammatory mediator, platelet activating factor (PAF) (Wissner et at., 1986, J. Med. Chem. 29: 329), suggesting a unique proinflammatory relationship between pneumococci and PAF in the pathogenesis of meningitis and pneumonia (Cabellos et al., supra).
As noted above, pneumococci adhere to glycoconjugates containing N-acetyl-D-galactosamine .beta.1-4 galactose (GalNAc.beta.1-4Gal) or GalNAc.beta.1-3Gal either in purified form or presented on the surfaces of resting vascular endothelial and pulmonary type II epithelial cells (Krivan et al., 1988, Proc. Natl. Acad. Sci. USA 85: 6157). However, the local generation of inflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin-1 (IL-1), during the course of infection can dramatically alter the presentation of potential receptors on cells (Rozdzinski et al., 1993, J. Exp. Med. 178: 917; van de Kar et at., 1992, Blood 11: 2725). For example, activation of vascular endothelial cells by TNF and IL-1 stimulates the synthesis of PAF (Bussolino et at., 1988, Biochim. Biophys. Acta 927: 43; Chao and Olson, 1993, Biochem. J. 292: 617; Zimmerman et al., 1992, Immunol. Today 13: 93-100) and increases expression of a variety of cell surface receptors including E-selectin (Rozdzinski et al., supra) and globotriosylceramide (van de Kar et al., supra).
Thus, there is a need in the art to identify ligands for bacterial adherence. There is a particular need in the art to identify such ligands on cells activated by inflammatory mediators. There is yet a further need to further characterize the role of pneumococci in inflammatory processes associated with pneumococcal infections.
The citation of references herein shall not be construed as an admission that such is prior art to the present invention.